A key role of GARP in the immune suppressive tumor microenvironment
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Susanne A. Hahn1, Annemarie Neuhoff1, Jenny Landsberg6, Jonathan Schupp1, Daniela Eberts4, Petra Leukel3, Matthias Bros1, Martin Weilbaecher1, Detlef Schuppan2,5, Stephan Grabbe1, Thomas Tueting6, Volker Lennerz4, Clemens Sommer3, Helmut Jonuleit1 and Andrea Tuettenberg1
1 Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
2 Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg-University, Mainz, Germany
3 Institute of Neuropathology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
4 Department of Medicine II, University Medical Center, Johannes Gutenberg-University, Mainz, Germany
5 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
6 Department of Dermatology, University Medical Center, Bonn, Germany
Susanne A. Hahn, email:
Keywords: Treg, melanoma, GARP, tumor microenvironment, tolerance
Received: May 03, 2016 Accepted: May 14, 2016 Published: May 27, 2016
In melanoma patients, one of the main reasons for tumor immune escape and therapy failure is the immunosuppressive tumor microenvironment. Herein, suppressive immune cells and inhibitory factors secreted by the tumor itself play a central role.
In the present study we show that the Treg activation marker GARP (glycoprotein A repetitions predominant), known to induce peripheral tolerance in a TGF-β dependent way, is also expressed on human primary melanoma. Interestingly, membrane bound GARP is shed from the surface of both, activated Treg and melanoma cells, and, in its soluble form (sGARP), not only induces peripheral Treg but also a tumor associated (M2) macrophage phenotype. Notably, proliferation of cytotoxic T cells and their effector function is inhibited in the presence of sGARP. GARP expression on Treg and melanoma cells is significantly decreased in the presence of agents such as IFN-α, thus explaining at least in part a novel mechanism of action of this adjuvant therapy.
In conclusion, GARP in its soluble and membrane bound form contributes to peripheral tolerance in a multipronged way, potentiates the immunosuppressive tumor microenvironment and thus acts as a negative regulator in melanoma patients. Therefore, it may qualify as a promising target and a new checkpoint for cancer immunotherapy.
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